Our hypothesis is that bone remodeling and the control of bone formation and bone resorption is regulated by local factors in the bone microenvironment. One factor likely to be involved in the regulation of these events is transforming growth factor beta (TGF beta), which is abundant in bone and whose activity in media bathing bone cultures is modulated by bone resorbing hormones. We have found recently that TGF beta is released from bone bound to one or more binding proteins which appear to regulate its activity. These binding proteins form a latent complex with TGF beta and interfere with its biological activity by blocking the binding of the molecule to its receptor. The bone-derived binding protein is different from the binding protein for TGF beta in platelets. This latent complex is dissociated by acid conditions. Since acid production by osteoclasts is required for the resorption process, this suggests that the release of active bone-derived TGF beta from its binding proteins can be regulated by osteoclast function. In this project, the goals are to identify the bone-derived binding protein(s) for TGF beta which appear to regulate its activity, and to determine their relationship to alpha 2 macroglobulin and to the precursor for TGF beta. We will also determine the mechanism of action of bone-derived TGF beta, and how this activation process is regulated. We believe that understanding the relationship between bone-derived TGF beta and the binding protein which controls the biological activity of TGF beta will prove to be important for understanding the relationship between osteoblastic bone formation and previous bone resorption.